Punctal plugs for the delivery of active agents

ABSTRACT

The invention provides punctal plugs for the delivery of active agent to one or both of the tear fluid of the eye and to the nasolacrimal duct. The plugs of the invention have a body, a reservoir contained within the body, and optionally a collarette. The reservoir has at least one opening and contains a polymeric material and at least one active agent.

RELATED APPLICATIONS

This application claims priority from provisional application U.S. Ser.No. 60/805,378 filed on Jun. 21, 2006.

FIELD OF THE INVENTION

The present invention relates to devices suitable for deliveringsubstances to one or more of the eye, nose and throat. In particular,the invention relates to punctal plugs for delivery of at least oneactive agent.

BACKGROUND OF THE INVENTION

Human tears are secreted by the lacrimal gland and flow across thesurface of the eye to a shallow pool, known as the lacrimal lake,located where the eyelids come together at their inner ends. From there,the tears drain through small openings in each of the upper and lowereyelids, termed the superior lacrimal punctum and the inferior lacrimalpunctum, respectively. From the superior and inferior puncta, the tearspass into each of the superior and inferior lacrimal canaliculus,respectively, which are duct-like pathways that lead to the lacrimalsac. The lacrimal sac is the superior, expanded portion of thenasolacrimal duct, which drains tears into the nasal system. Activeagents can thus be delivered to the nose and throat through the lacrimalcanaliculi, which lead into the nasolacrimal duct.

Active agents frequently are administered to the eye for the treatmentof ocular diseases and disorders. Conventional means for deliveringactive agents to the eye involve topical application to the surface ofthe eye. The eye is uniquely suited to topical administration because,when properly constituted, topically applied active agents can penetratethrough the cornea and rise to therapeutic concentration levels insidethe eye. Active agents for ocular diseases and disorders may beadministered orally or by injection, but such administration routes aredisadvantageous in that, in oral administration, the active agent mayreach the eye in too low a concentration to have the desiredpharmacological effect and their use is complicated by significant,systemic side effects, while injections pose the risk of infection.

The majority of ocular active agents are currently delivered topicallyusing eye drops which, though effective for some applications, areinefficient. When a drop of liquid is added to the eye, it overfills theconjunctival sac, the pocket between the eye and the lids, causing asubstantial portion of the drop to be lost due to overflow of the lidmargin onto the cheek. In addition, a substantial portion of the dropthat remains on the ocular surface is drained into the lacrimal puncta,diluting the concentration of the drug.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a sectional view of a punctal plug having a body 10 with anenlarged segment 12 and a reservoir 15 within the body 10 that containsa polymeric material 11 that contains active agent 18. The reservoir 15has an opening 13 through which the active agent 18 is released.

FIG. 2 is a sectional view of a punctal plug having a body 20 with anenlarged segment 22 and a reservoir 25 within the body 20 that containsa polymeric material 21 that contains active agent 28. The reservoir 25has an opening 23 through which the active agent 28 is released.

FIG. 3 is a sectional view of a punctal plug having a body 30 with anenlarged segment 32 and a reservoir 35 within the body 30 that containsa polymeric material 31 that contains active agent 38. The reservoir 35has two openings 33 and 33′ through which the active agent 38 isreleased.

FIG. 4 is a sectional view of a punctal plug having a body 40 with anenlarged segment 42, a reservoir 45 within the body 40 that contains apolymeric material 41 that contains active agent 48, and a collarette44. The reservoir 45 has an opening 43 through which the active agent 48is released.

FIG. 5 is a sectional view of a punctal plug having a body 50 with anenlarged segment 52, a reservoir 55 within the body 50 that contains apolymeric material 51 that contains active agent 58, and a collarette54. The reservoir 55 has an opening 53 through which the active agent 58is released.

FIG. 6 is a sectional view of a punctal plug having a body 60 with anenlarged segment 62, a reservoir 65 within the body 60 that contains apolymeric material 61 that contains active agent 68, and a collarette64. The reservoir 65 has two openings 63 and 63′ through which theactive agent 68 is released.

FIG. 7 is a sectional view of a punctal plug having a body 70 made of aflexible polymeric material, a reservoir 75 within the body 70 that iscoterminous with the body 70, and a collarette 74. The reservoir 75contains a polymeric material 71 that contains active agent 78, and thereservoir 75 has an opening 73 through which the active agent 78 isreleased.

FIG. 8 is a sectional view of a punctal plug having a body 80 made of aflexible polymeric material, a reservoir 85 within the body 80 that iscoterminous with the body 80, and a collarette 84. The reservoir 85contains a polymeric material 81 that contains active agent 88, and thereservoir 85 has two openings 83 and 83′ through which the active agent88 is released.

FIG. 9 is a three-dimensional view of the punctal plug depictedtwo-dimensionally in FIG. 4 having a body 90 with an enlarged segment92, a reservoir 95 within the body 90 that contains a polymeric material91 that contains active agent 98, and a collarette 94. The reservoir 95has an opening 93 through which the active agent 98 is released.

FIG. 10 is a sectional view of a punctal plug having a body 100 with anenlarged segment 102, a reservoir 105 within the body 100, a collarette104, and a tapering, rounded end 103. The reservoir 105 contains apolymeric material 101 that contains active agent 108, and the reservoir105 has openings 103 through which the active agent 108 is released.

FIG. 11 is a graph depicting the active agent release profile for thepunctal plug of Example 2.

FIG. 12 is a graph depicting the active agent release profile for thepunctal plug of Example 3.

DETAILED DESCRIPTION OF THE INVENTION AND ILLUSTRATIVE EMBODIMENTS

The present invention provides punctal plugs that can be used to deliveractive agents to one or both of the nasolacrimal duct and to the tearfluid of the eye. In one embodiment, the invention provides punctalplugs comprising, consisting essentially of, and consisting of: a bodyhaving a first end and a second end; a lateral surface extending betweenthe two ends; a reservoir contained within the body wherein thereservoir comprises, consists essentially of and consists of at leastone opening and contains a material that comprises, consists essentiallyof and consists of at least one active agent; and wherein the body isimpermeable to the active agent.

Referring to FIG. 1, punctal plug body 10 has a reservoir 15 thatcontains at least one opening 13 and active agent 18 is released throughopening 13, for example, when the active agent-containing material 11,preferably a polymeric material, dissolves, degrades, or the activeagent 18 simply diffuses or is released from material 11, depending uponthe nature of the material. The opening through which the active agentis released from the plug may be located at a first end, as for examplein FIG. 1, a second end as for example in FIG. 2, or both the first andsecond ends of the plug body as for example shown in FIG. 3, or alongthe lateral surface thereof. Preferably, the opening is located at oneor both of the first and second ends. In particular embodiments of theinvention, for example as shown in FIG. 3, the punctal plug contains anenlarged segment 32 of the body 30 that is of a suitable size and shapefor securing the punctal plugs in the lacrimal canaliculus.

For delivery of an active agent into the tear fluid of the eye, apunctal plug is inserted into a lacrimal canaliculus and the activeagent is released into the tear fluid of the eye. Referring to FIG. 4,for delivery into the tear fluid, a collarette 44 is preferably providedon body 40 of the punctal plug and, when the punctal plug is insertedinto the lacrimal canaliculus, the collarette 44 rests on the exteriorof the lacrimal punctum. For delivery of active agent into thenasolacrimal duct, a punctal plug is inserted, preferably deeply, intothe lacrimal canaliculus and the active agent is released into thenasolacrimal duct.

As used herein, the term “punctal plug” refers to a device of a size andshape suitable for insertion into the inferior or superior lacrimalcanaliculus of the eye through the inferior or superior lacrimalpunctum.

As used herein, the term “active agent” refers to an agent capable oftreating, inhibiting, or preventing a disorder or a disease. Exemplaryactive agents include, without limitation, pharmaceuticals andnutraceuticals. Preferred active agents are capable of treating,inhibiting, or preventing a disorder or a disease of one or more of theeye, nose and throat.

As used herein, the phrase “a material that is at least partiallywater-soluble” refers to a material that exhibits a level of solubilityin water sufficient to result in detectable dissolution of the materialupon exposure to an aqueous environment.

As used herein, the phrase “a material that is biodegradable” refers toa material that degrades to a detectable degree upon exposure tobiologically active substances typically present in mammals.

As used herein, the phrase “a material that is insoluble in water”refers to a material that does not dissolve to a substantial degree uponexposure to water.

As used herein, the phrase “a material that is non-biodegradable” refersto a material that does not degrade to a substantial degree uponexposure to biologically active substances typically present in mammals.

As used herein, the phrase “body that is impermeable to active agent”refers to a body through which only an insubstantial amount of activeagent can pass.

As used herein, the term “polymeric material” refers to a material madeof one or more types of polymers that is capable of containing at leastone active agent and releasing the active agent, for example, when thepolymers dissolve or degrade, when the active agent diffuses from thepolymers, or when a pro-drug is used in which the active agent isattached to the polymers and then released by being cleaved from thematerial.

As used herein, the term “opening” refers to an opening in the body of apunctal plug of a size and shape through which the active agent canpass. Preferably, only the active agent can pass through the opening.The opening, for example, may be a hole covered with a membrane, mesh,grid or it may be uncovered. The membrane, mesh, or grid may be one ormore of porous, semi-porous, permeable, semi-permeable, andbiodegradable.

As used herein, the phrase “flexible material” refers to a material thatis not rigid and that substantially conforms to the surface of whateverobject the material contacts.

As used herein, the phrase “the reservoir and the body are coterminous”indicates that the reservoir is substantially all of the body. Acollarette can be attached to the body when the reservoir and body arecoterminous, but the collarette would not considered to be part of thebody.

As used herein, the phrase “refilled with active agent” refers to addingany detectable amount of active agent to the reservoir of a punctalplug.

The present invention encompasses numerous punctal plugs for thedelivery of active agents to one or both of the tear fluid of the eyeand to the nasolacrimal duct. The punctal plugs preferably are insertedinto the inferior lacrimal canaliculus, the superior lacrimalcanaliculus, or both the inferior and superior lacrimal canaliculi. Ifthe punctal plugs are being used to deliver active agents to the tearfluid of the eye, the punctal plugs preferably have a collarette at oneend of the body. The collarette is a portion of the punctal plug thatextends radially outwardly from one end of the body to a degreesufficient, and having a size and a shape, such that at least a portionof the collarette will extend beyond and be exterior to the lacrimalpunctum after insertion of the punctal plug into the lacrimalcanaliculus. Typically, the collarette will extend about 0#.2 to about 1mm beyond the plug body. The portion of the punctal plug without thecollarette is inserted into one of the inferior lacrimal punctum or thesuperior lacrimal punctum. Referring to FIG. 6, enlarged segment 62 andbody 60 is inserted into one of the punctum, and collarette 64 restsagainst the exterior of the lacrimal punctum and keeps the punctal plugfrom slipping down into the lacrimal canaliculus, so that contactbetween the punctal plug and the tear fluid of the eye is maintained.

If the punctal plugs are being used to deliver active agent to thenasolacrimal duct, the punctal plugs may not have a collarette so thatthey may be inserted at a sufficient depth within one or both of thelacrimal canaliculi such that the active agent is released into thelacrimal sac. In FIGS. 1 through 3 are depicted examples of punctalplugs useful for delivery of an active agent into the nasolacrimal duct.

The numerous punctal plugs of the invention each have various featuresand advantages. For example, certain punctal plugs have a body with afirst end, a second end, and a lateral surface extending between the twoends. The lateral surface preferably has an outer diameter that issubstantially circular in shape and, thus, the body preferably has acylindrical shape. A portion of the lateral surface of certain of thepunctal plugs preferably has an outer diameter that is greater than theouter diameter of the remainder of the lateral surface. With referenceto FIG. 2, the enlarged portion 22 of the lateral surface anchors orsecures the punctal plugs in the lacrimal canaliculus. The enlargedportion can be any size or shape, and can be present on any part of thelateral surface, so long as the enlarged portion at least partiallyanchors the punctal plug in the lacrimal canaliculus. Preferably, theenlarged portion is at one end of the plug. Conveniently, the enlargedportion may take the shape of an inverted triangle having a flattenedapex, as shown in FIG. 1, may have an untapered, body rounded at theend, or may have a tapered shape at one end with a rounded point asshown in FIG. 10. One ordinarily skilled in the art will recognize thatany of a wide variety of shapes are possible.

The body of the punctal plugs of the invention may take any shape andsize, Preferably, the body is in the shape of an elongated cylinder. Thebody will be about 0#.8 to about 5 mm in length, preferably about 1#.2to about 2#.5 mm in length. The width of the body will be about 0#.2 toabout 3, preferably 0#.3 to about 1#.5 mm.

The body of the plug may be wholly or partially transparent or opaque.Optionally, the body may include a tint or pigment that makes the plugeasier to see when it is placed in a punctum.

The body of the punctal plugs may be made of any suitable biocompatiblematerial including, without limitation, silicone, silicone blends,silicone co-polymers, such as, for example, hydrophilic monomers ofpolyhydroxyethlymethacrylate (“pHEMA”), polyethylene glycol,polyvinylpyrrolidone, and glycerol, and silicone hydrogel polymers suchas, for example, those described in U.S. Pat. Nos. 5,962,548, 6,020,445,6,099,852, 6,367,929, and 6,822,016, incorporated herein in theirentireties by reference. Other suitable biocompatible materials include,for example: polyurethane; polymethylmethacrylate; poly(ethyleneglycol); poly(ethylene oxide); poly(propylene glycol); poly(vinylalcohol); poly(hydroxyethyl methacrylate); poly(vinylpyrrolidone)(“PVP”); polyacrylic acid; poly(ethyloxazoline); poly(dimethylacrylamide); phospholipids, such as, for example, phosphoryl cholinederivatives; polysulfobetains; acrylic esters, polysaccharides andcarbohydrates, such as, for example, hyaluronic acid, dextran,hydroxyethyl cellulose, hydroxyl propyl cellulose, gellan gum, guar gum,heparan sulfate, chondritin sulfate, heparin, and alginate; proteinssuch as, for example, gelatin, collagen, albumin, and ovalbumin;polyamino acids; fluorinated polymers, such as, for example,polytetrafluoroethylene (“PTFE”), polyvinylidene fluoride (“PVDF”), andteflon; polypropylene; polyethylene; nylon; and ethylene vinyl alcohol(“EVA”).

The surface of the plug body may be wholly or partially coated. Thecoating may provide one or more of lubriciousness to aid insertion,muco-adhesiveness to improve tissue compatibility, and texture to aid inanchoring the plug within the punctum. Examples of suitable coatingsinclude, without limitation, gelatin, collagen, hydroxyethylmethacrylate, PVP, PEG, heparin, chondroitin sulphate, hyaluronic acid,synthetic and natural proteins, and polysaccharides, thiomers, thiolatedderivatives of polyacrylic acid and chitosan, polyacrylic acid,carboxymethyl cellulose and the like and combinations thereof.

Certain embodiments of the punctal plugs of the invention have a bodymade of a flexible material that conforms to the shape of whatever itcontacts. Optionally, the plug may have a collarette formed of either aless flexible material than that of the body or material that tooconforms to the shape of whatever it contacts. When a punctal plughaving both a flexible body and a less flexible collarette is insertedinto the lacrimal canaliculus, the collarette rests on the exterior ofthe lacrimal punctum and the body of the punctal plug conforms to theshape of the lacrimal canaliculus. The reservoir and the body of suchpunctal plugs are preferably coterminous. That is, the reservoir of suchpunctal plugs preferably make up the entirety of the body, except forthe collarette.

In embodiments in which one or both of a flexible body and collaretteare used, the flexible body and flexible collarette can be made ofmaterials that include, without limitation, nylon, polyethyleneterephthalate (“PET”), polybutlylene terephthalate (“PBT”),polyethylene, polyurethane, silicone, PTFE, PVDF, and polyolefins.Punctal plugs made of nylon, PET, PBT, polyethylene, PVDF, orpolyolefins are typically manufactured for example and withoutlimitation, extrusion, injection molding, or thermoforming. Punctalplugs made of latex, polyurethane, silicone, or PTFE are typicallymanufactured using solution casting processes.

The punctal plugs of the invention contain a reservoir within the body,and the reservoir contains an active agent-containing material. Thematerial may be any material that is compatible with the active agent oragents to be delivered by the plug and is capable of releasing theactive agent in the desired manner, for example by dissolving ordegrading of the material or diffusion of the active agent from thematerial. Any number of material may be used as the activeagent-containing material including, without limitation, polymericmaterials, both naturally occurring and synthetic, non-polymericmaterials including, without limitation, glasses and clays, organicmaterials, inorganic materials including, without limitation, porousceramics, lipids, waxes and the like and combinations thereof.Preferably, the active agent containing-material is a polymericmaterial, in which at least one active agent is disposed on, dispersedthroughout, or otherwise contained. The body is preferably impermeableto the active agent, and the reservoir has at least one opening throughwhich the active agent is released.

The body has one or more openings communicating with the reservoir at afirst end, as shown in FIG. 4, a second end a shown in FIG. 5, both thefirst and second ends of the body as shown in FIG. 6, or at anotherlocation on the body. In particular embodiments of the invention, whensuch punctal plugs are inserted into the lacrimal canaliculus and haveopening at the end of the body facing the eye, the active agent isreleased into the tear fluid of the eye. Alternatively, if the plug hasan opening in the end of the body facing the nasolacrimal duct, theactive agent is released into the nasolacrimal duct. In thoseembodiments in which the plug has opening at the end of the body facingthe eye and another opening at the end of the body facing thenasolacrimal duct, the active agent is released into both the tear fluidof the eye and the nasolacrimal duct. For those punctal plugs with acollarette, the opening of such punctal plugs is preferably locatedwithin the collarette, preferably the central portion of the collarette.When such punctal plugs are inserted into the lacrimal canaliculus, theopening faces the eye, and the active agent is released into the tearfluid of the eye.

The size of the opening will be from about 1 nm to about 2#.5 mm andpreferably about 0#.15 mm to about 0#.8 mm. Instead of one large openingat any one location, multiple small openings may be used.

Processes for manufacturing the punctal plugs useful in the inventionare well known. Typically, the plugs are manufactured by injectionmolding, cast molding, transfer molding or the like. Preferably, thereservoir is filled with one or both of at least one active agent andthe active agent-containing material subsequent to the manufacture ofthe plug. Additionally, one or more excipients may be combined with theactive agent alone or in combination with the polymeric material.

Depending upon the active agent-containing material selected, the activeagent can be released from the material almost immediately, or theactive agent can be released in a sustained manner over a desired periodof time. For example, a polymeric material may be used that is composedof one or more polymers that are at least partially soluble in water.When such a polymeric material is exposed to the aqueous environment ofthe lacrimal canaliculus or the tear fluid, it preferably will dissolveand release the active agent as it dissolves. The solubility in water ofthe one or more polymers from which the polymeric material is madetypically will be directly proportional to its rate of dissolution.Suitable polymers that are at least partially soluble in water include,without limitation, poly(ethylene glycol); poly(ethylene oxide);poly(propylene glycol); poly(vinyl alcohol); poly(hydroxyethylmethacrylate); poly(vinylpyrrolidone); polyacrylic acid;poly(ethyloxazoline); poly(dimethyl acrylamide); phosolipids, such as,for example, phosphoryl choline derivatives; polysulfobetains;polysaccharides and carbohydrates, including, without limitation,hyaluronic acid, dextran, hydroxyethyl cellulose, hydroxyl propylcellulose, gellan gum, guar gum, heparan sulfate, chondritin sulfate,heparin, and alginate; proteins such as, for example, gelatin, collagen,albumin, and ovalbumin; and polyamino acids. The polymeric materials inthis list can typically be copolymerized or blended with one or both ofhydrophobic polymers and monomers.

As an alternative, a non-polymeric material including, withoutlimitation, a lipid, wax, or inorganic material may be used. Suitablenon-polymeric materials include, without limitation, lanolin, paraffin,sorbates, lecithin, vitamin A, D, and E, glycerine, sorbitol, mannitol,stearates, fatty acids, lutein, zeaxanthin, taurine, glutathione and thelike.

Alternatively, the active agent-containing material can be one or morebiodegradable polymers that partially or wholly chemically degrade uponexposure to, for example, biologically active substances typicallypresent in mammals. The biodegradable materials are preferablyhydrolyzable under in vivo conditions. Biodegradation may occur moreslowly than dissolution, and the material can thus compose one or morebiodegradable polymers if slower, more sustained release of the activeagent is desired.

Suitable biodegradable polymers include, without limitation, polymersand oligomers of glycolide, lactide, lactones, and other hydroxy acids,and other biologically degradable polymers that yield materials that arenon-toxic or present as normal metabolites in the body. Preferredpoly(alpha-hydroxy acids) are poly(glycolic acid), poly(2-dioxanone);poly(DL-lactic acid) and poly(L-lactic acid). Other useful polymersinclude poly(amino acids), polycarbonates, poly(anhydrides),poly(orthoesters), poly(phosphazines) and poly(phosphoesters).Polylactones including, without limitation, poly(epsilon-caprolactone),poly(delta-caprolactone), poly(delta-valerolactone) andpoly(gamma-butyrolactone are also useful, as are chitosan, alginates,collagen, and gelatin. In particular aspects of the invention, thepolymeric material the contains the active agent can comprise a mixtureof one or more dissolvable and bio-degradable polymers.

In a preferred embodiment, the active agent-containing material is apolymeric material that is combined with at least one active agent toform one or more fiber or fiber-like structures, the dimensions of whichmay be substantially the dimensions of the reservoir or smaller thansuch dimensions, and one or more of the fibers or fiber-like structuresare inserted into the reservoir through the opening in the plug body.The fibers or fiber-like structures may be of a size and a shapesuitable for insertion into the opening and may be about 0#.5 to about 5mm in length and 0#.05 to about 2 mm in diameter. If only one fiber orfiber-like structure is used, preferably, the dimensions of the fiberare such that the fiber fits securely into the reservoir and remains inthe reservoir when the plug is in use in a wearer's punctum. Thus, thefiber can be symmetrical or asymmetrical, depending upon the shape ofthe reservoir. The internal walls of the reservoir may be substantiallysmooth or may include features that aid in maintaining the fiber withinthe reservoir including, without limitation, surfaces with grooves,indentations, roughness or the like in the interior walls.

Alternatively, the fiber containing the active agent or agents may beformed and the plug cast around the fiber. As yet another alternative,the fiber and active agent may be dosed into the plug reservoir as amelt and allowed to solidify. As still another alternative, the polymerand active agent may be introduced as a solution. The solution maycontain monomers, pre-polymers and the like suitable for cross-linkingvia one or more of irradiation, redox, and thermal radicalpolymerization. As yet another alternative, the fiber may simply besoaked in the active agent before or after insertion in the plug.

Preferably the fiber or fiber-like structures are composed of apolymeric material and more preferably a polymeric material that ispolycaprolactone, still more preferably poly(epsilon-caprolactone), andethylene vinyl acetate of molecular weights between about 10,000 and80,0000. About 0 to about 100 weight percent polycaprolactone and about100 to about 0 weight percent of the ethylene vinyl acetate are usedbased on the total weight of the polymeric material and, preferably,about 50% each of polycaprolactone and ethylene vinyl acetate is used.The polymeric material used is preferably greater than about 99% pureand the active agents is preferably greater than about 97% pure. One ofordinary skill in the art will recognize that in compounding, theconditions under which compounding is carried out will need to take intoaccount the characteristics of the active agent to ensure that theactive agents do not become degraded by the process. Thepolycaprolactone and ethylene vinyl acetate preferably are combined withthe desired active agent or agents, micro-compounded, and then extrudedas a fiber. The fibers are then cut to the desired length and insertedinto the reservoir through one or more plug openings.

The amount of active agent used in the plugs of the invention willdepend upon the active agent or agents selected, the desired doses to bedelivered via the punctual plug, the desired release rate, and themelting points of the active agent and active agent-containing material.Preferably, the amount used is a therapeutically effective amountmeaning an amount effective to achieve the desired treatment,inhibitory, or prevention effect. Typically, amounts of about 0#.05 toabout 8,000 micrograms of active agents may be used.

In certain aspects of the invention, the reservoir can be refilled witha material after substantially all of the active agent-containingmaterial has dissolved or degraded and the active agent is released. Forexample, the new active agent-containing material can be the same as, ordifferent from, the previous polymeric material, and can contain atleast one active agent that is the same as, or different from theprevious active agent. Certain punctal plugs used for particularapplications can preferably be refilled with a material while thepunctal plugs remain inserted in the lacrimal canaliculus, while otherpunctal plugs are typically removed from the lacrimal canaliculus, a newmaterial is added, and the punctal plugs are then reinserted into thelacrimal canaliculus.

When the active agent-containing material is combined with the activeagent, the material may also contain one or more materials that areinsoluble in water and non-biodegradable, but from which the activeagent can diffuse. For example, if the material is a polymeric material,the material may be composed of one or more polymers that are insolublein water and non-biodegradable. Suitable polymers of this type include,for example, cross-liked polymers, such as, for example, cross-linkedpoly(ethylene glycol), poly(ethylene oxide), poly(propylene glycol),poly(vinyl alcohol), poly(hydroxyethyl methacrylate),poly(vinylpyrrolidone), polyacrylic acid, poly(ethyloxazoline), andpoly(dimethyl acrylamide). These polymers can be copolymerized orblended with one or both of hydrophobic polymers and monomers.Additional polymers that are insoluble in water and non-biodegradableinclude, without limitation, silicone; silicone blends; siliconeco-polymers including, without limitation, hydrophilic monomers ofpHEMA, polyethylene glycol, polyvinylpyrrolidone, and glycerol; siliconehydrogel polymers such as, for example, those described in U.S. Pat.Nos. 5,962,548, 6,020,445, 6,099,852, 6,367,929, and 6,822,016,incorporated herein in their entireties by reference; phosolipidsincluding, without limitation, phosphoryl choline derivatives;polysulfobetains; polysaccharides and carbohydrates including, withoutlimitation, hyaluronic acid, dextran, hydroxyethyl cellulose, hydroxylpropyl cellulose, gellan gum, guar gum, heparan sulfate, chondritinsulfate, and heparin; proteins including, without limitation, albuminand ovalbumin; polyamino acids; fluorinated polymers including, withoutlimitation, PTFE, PVDF, and teflon; polypropylene; polyethylene; nylon;and EVA. Additional examples of suitable polymers that are either orboth insoluble in water and non-biodegradable include, withoutlimitation, silicones, polyurethanes, cyanoacrylates, and polyacrylicacid.

The punctal plugs described herein can be used to deliver various activeagents for the one or more of the treatment, inhibition, and preventionof numerous diseases and disorders. Each punctal plug can be used todeliver at least one active agent and can be used to deliver differenttypes of active agents. For example, the punctal plugs can be used todeliver azelastine HCl, emadastine difumerate, epinastine HCl, ketotifenfumerate, levocabastine HCl, olopatadine HCl, pheniramine maleate, andantazoline phosphate for one or more of the treatment, inhibition, andprevention of allergies. The punctal plugs can be used to deliver mastcell stabilizers, such as, for example, cromolyn sodium, lodoxamidetromethamine, nedocromil sodium, and permirolast potassium.

After the plugs is filled with the active agent, the plug is sterilizedby any convenient method including, without limitation, ethylene oxide,autoclaving, irradiation, and the like and combination thereof.Preferably, sterilization is carried out through gamma radiation or useof ethylene oxide.

The punctal plugs can be used to deliver mydriatics and cycloplegicsincluding, without limitation, atropine sulfate, homatropine,scopolamine HBr, cyclopentolate HCl, tropicamide, and phenylephrine HCl.The punctal plugs can be used to deliver ophthalmic dyes including,without limitation, rose begal, sissamine green, indocyanine green,fluorexon, and fluorescein.

The punctal plugs can be used to deliver corticosteroids including,without limitation, dexamethasone sodium phosphate, dexamethasone,fluoromethalone, fluoromethalone acetate, loteprednol etabonate,prednisolone acetate, prednisolone sodium phosphate, medrysone,rimexolone, and fluocinolone acetonide. The punctal plugs can be used todeliver non-steroidal anti-inflammatory agents including, withoutlimitation, flurbiprofen sodium, suprofen, diclofenac sodium, ketorolactromethamine, cyclosporine, rapamycin methotrexate, azathioprine, andbromocriptine.

The punctal plugs can be used to deliver anti-infective agentsincluding, without limitation, tobramycin, moxifloxacin, ofloxacin,gatifloxacin, ciprofloxacin, gentamicin, sulfisoxazolone diolamine,sodium sulfacetamide, vancomycin, polymyxin B, amikacin, norfloxacin,levofloxacin, sulfisoxazole diolamine, sodium sulfacetamidetetracycline, doxycycline, dicloxacillin, cephalexin,amoxicillin/clavulante, ceftriaxone, cefixime, erythromycin, ofloxacin,azithromycin, gentamycin, sulfadiazine, and pyrimethamine.

The punctal plugs can be used to deliver agents for the one or more ofthe treatment, inhibition, and prevention of glaucoma including, withoutlimitation, epinephrines, including, for example: dipivefrin; alpha-2adrenergic receptors, including, for example, aproclonidine andbrimonidine; betablockers including, without limitation, betaxolol,carteolol, levobunolol, metipranolol, and timolol; direct miotics,including, for example, carbachol and pilocarpine; cholinesteraseinhibitors, including, without limitation, physostigmine andechothiophate; carbonic anhydrase inhibitors, including, for example,acetazolamide, brinzolamide, dorzolamide, and methazolamide;prostoglandins and prostamides including, without limitation,latanoprost, bimatoprost, uravoprost, and unoprostone cidofovir.

The punctal plugs can be used to deliver antiviral agents, including,without limitation, fomivirsen sodium, foscarnet sodium, ganciclovirsodium, valganciclovir HCl, trifluridine, acyclovir, and famciclovir.The punctal plugs can be used to deliver local anesthetics, including,without limitation, tetracaine HCl, proparacaine HCl, proparacaine HCland fluorescein sodium, benoxinate and fluorescein sodium, and benoxnateand fluorexon disodium. The punctal plugs can be used to deliverantifungal agents, including, for example, fluconazole, flucytosine,amphotericin B, itraconazole, and ketocaonazole.

The punctal plugs can be used to deliver analgesics including, withoutlimitation, acetaminophen and codeine, acetaminophen and hydrocodone,acetaminophen, ketorolac, ibuprofen, and tramadol. The punctal plugs canbe used to deliver vasoconstricors including, without limitation,ephedrine hydrochloride, naphazoline hydrochloride, phenylephrinehydrochloride, tetrahydrozoline hydrochloride, and oxymetazoline.Finally, the punctal plugs can be used to deliver vitamins,antioxidants, and nutraceuticals including, without limitation, vitaminsA, D, and E, lutein, taurine, glutathione, zeaxanthin, fatty acids andthe like.

The active agents delivered by the punctal plugs can be formulated tocontain excipients including, without limitation, synthetic and naturalpolymers, including, for example, polyvinylalcohol, polyethyleneglycol,PAA (polyacrylic acid), hydroxymethyl cellulose, glycerine, hypromelos,polyvinylpyrrolidone, carbopol, propyleneglycol, hydroxypropyl guar,glucam-20, hydroxypropyl cellulose, sorbitol, dextrose, polysorbate,mannitol, dextran, modified polysaccharides and gums, phosolipids, andsulphobetains.

The invention will be clarified further by consideration of thefollowing, non-limiting examples.

EXAMPLES Example 1

A 1#.50 g amount of epsilon polycaprolactone with an average M_(w) ofapproximately 14,000 and an average M_(n) of approximately 10,000 by GPC(available from Aldrich) was combined with 1#.50 g EVA (EVATANE™,Arkema), and 1#.00 g of bimatoprost (Cayman Chemicals), each with apurity of greater than approximately 97%. The mixture was then placed ina twin-screw micro-compounder Model No. 20000 from DACA Industries, Inc.that was fitted with a 0#.25 mm die and compounded for 15 min. at 120rpm and 67° C#. Following compounding, the mixture was extruded intofibers at 75° C#.

The fibers were cut into approximately 1#.5 mm in length sections andinserted into the opening of Sharpoint ULTRA™ plug, available fromSurgical Specialties. 70 plugs with drug and 30 placebo each of a 0#.6mm length were made and 70 drugs with drug and 50 placebo each of a 0#.8mm length were made. To insert the fiber, each plug was positioned undera stereomicroscope and tweezers were used to insert a fiber into theopening of each of the plugs. Each plug was then placed in a glass vialand packed in a pouch. Gamma radiation sterilization was then performedwith a total does of 15 Kgy at about 0#.2 Kgy/min.

Example 2

A plug made according to the method of Example 1 that is 0#.6 mm inlength and a fiber having a diameter of approximately 0#.2 mm andcontaining 25% w/w was placed in a glass vial with 1 cc of phosphatebuffered saline having a pH of 7#.4. The vial was placed in an incubatorat 37° C#. and gently agitated. Aliqouts of 1 cc were collected atintervals at 3, 8, and 24 hours and then weekly and analyzed for drugcontent via HPLC. FIG. 11 is a graph depicting the results of theanalysis.

Example 3

A plug made according to the method of Example 1 that is 0#.9 mm inlength and a fiber with an approximately 0#.6 mm diameter and containing25% was placed in a glass vial with 1 cc of phosphate buffered salinehaving a pH of 7#.4. The vial was placed in an incubator at 37° C#. andgently agitated. Aliqouts of 1 cc were collected at intervals as setforth in Example 2 and analyzed for drug content via HPLC. FIG. 12 is agraph depicting the results of the analysis.

1. A punctal plug, comprising: a body having a first end, a second end,and a lateral surface extending between the two ends; a reservoircontained within the body, wherein the reservoir comprises at least oneopening, and contains an active agent-containing material that comprisesat least one active agent; and wherein the body is impermeable to theactive agent.
 2. A punctal plug, comprising: a body having a first end,a second end, and a lateral surface extending between the two ends; areservoir contained within the body, wherein the reservoir comprises anopening at the first end, the second end, or both the first and secondends of the body, and contains an active agent-containing material thatcomprises at least one active agent; and wherein the body is impermeableto the active agent.
 3. The punctual plug of claim 1, wherein thelateral surface of the body has an outer diameter that is substantiallycircular in shape and a portion of the lateral surface has an outerdiameter that is greater than that of the remainder of the lateralsurface
 4. The punctual plug of claim 2, wherein the lateral surface ofthe body has an outer diameter that is substantially circular in shapeand a portion of the lateral surface has an outer diameter that isgreater than that of the remainder of the lateral surface
 5. The punctalplug of claim 1, 2, 3, or 4, wherein the active agent-containingmaterial is at least partially water-soluble, dissolves over time, andreleases the active agent through an opening in the reservoir as itdissolves.
 6. The punctal plug of claim 1, 2, 3, or 4, wherein theactive agent-containing material is biodegradable, degrades over time,and releases the active agent through an opening in the reservoir as itdegrades.
 7. The punctal plug of claim 1, 2, 3, or 4, wherein the activeagent-containing material is insoluble in water and non-biodegradableand the active agent passively diffuses from the material through anopening in the reservoir.
 8. The punctal plug of claim 3, or 4, whereinthe portion of the lateral surface that has an outer diameter greaterthan that of the remainder of the lateral surface secures the punctalplug in a lacrimal canaliculus when the punctal plug is inserted in thelacrimal canaliculus.
 9. The punctal plug of claim 1, 2, 3, or 4,wherein when the punctal plug is inserted into a lacrimal canaliculus ofan eye, an opening in the reservoir faces the eye and the active agentis released into a tear fluid of the eye.
 10. The punctal plug of claim1, 2, 3, or 4, wherein when the punctal plug is inserted into a lacrimalcanaliculus of an eye, an opening in the reservoir faces a nasolacrimalduct and the active agent is released into the nasolacrimal duct. 11.The punctal plug of claim 1, 2, 3, or 4, wherein when the punctal plugis inserted into a lacrimal canaliculus of an eye, an opening in thereservoir faces the eye and the active agent is released into a tearfluid of the eye and another opening in the reservoir faces anasolacrimal duct and the active agent is also released into thenasolacrimal duct.
 12. A punctal plug for the delivery of active agentto the tear fluid of an eye and to a nasolacrimal duct, comprising: abody comprised of a flexible polymeric material that conforms to theshape of a lacrimal canaliculus when the punctal plug is inserted intothe lacrimal canaliculus; a reservoir contained within the body, whereinthe reservoir comprises at least one opening and contains an activeagent-containing material that comprises at least one active agent, andthe body is impermeable to the active agent; and a collarette that restson the exterior of the lacrimal punctum when the punctal plug isinserted into the lacrimal canaliculus.
 13. The punctal plug of claim12, wherein the active agent-containing material is at least partiallywater-soluble, dissolves over time, and releases the active agentthrough an opening in the reservoir as it dissolves.
 14. The punctalplug of claim 13, wherein the reservoir is refilled with a activeagent-containing material comprising at least one active agent that isthe same as or different from the previous active agent aftersubstantially all of the previous active agent-containing material hasdissolved.
 15. The punctal plug of claim 19, wherein the activeagent-containing material is biodegradable, degrades over time, andreleases the active agent through an opening in the reservoir as itdegrades.
 16. The punctal plug of claim 13, wherein the reservoir isrefilled with an active agent-containing material comprising at leastone active agent that is the same as or different from the previousactive agent after substantially all of the previous material hasdegraded.
 17. The punctal plug of claim 12, wherein the activeagent-containing material is insoluble in water and non-biodegradableand the active agent passively diffuses from the material through anopening in the reservoir.
 18. The punctal plug of claim 12, wherein thereservoir and the body are coterminous.
 19. The punctal plug of claim12, wherein when the punctal plug is inserted into the lacrimalcanaliculus an opening in the reservoir faces the eye and the activeagent is released into the tear fluid of the eye.
 20. The punctal plugof claim 12, wherein when the punctal plug is inserted into the lacrimalcanaliculus an opening in the reservoir faces the nasolacrimal duct andthe active agent is released into the nasolacrimal duct.
 21. The punctalplug of claim 12, wherein when the punctal plug is inserted into thelacrimal canaliculus an opening in the reservoir faces the eye and theactive agent is released into the tear fluid of the eye and anotheropening in the reservoir faces the nasolacrimal duct and the activeagent is also released into the nasolacrimal duct.
 22. A punctal plug,comprising: a body having a first end, a second end, and a lateralsurface extending between the two ends; a reservoir contained within thebody, wherein the reservoir comprises at least one opening, and containsan active agent-containing material that is a fiber or fiber-likestructure comprising at least one active agent; and wherein the body isimpermeable to the active agent.
 23. The punctual plug of claim 22,wherein the lateral surface of the body has an outer diameter that issubstantially circular in shape and a portion of the lateral surface hasan outer diameter that is greater than that of the remainder of thelateral surface
 24. The punctual plug of claim 22, wherein the reservoircontains a fiber that comprises about 0 to about 100 weight percent ofpolycaprolactone and about 100 to about 0 weigh percent of ethylenevinyl acetate.
 25. The punctual plug of claim 22, wherein the reservoircontains a fiber that comprises about 50 weight percent ofpolycaprolactone and about 50 weight percent of ethylene vinyl acetate.